Abstract CT136: An open-label phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy and in combination in patients with advanced hematological malignancies
Authors: Tomasz Knurowski, Emma Searle, Karen Clegg, Neil Pegg, William West, Debbie Haynes, Kristopher Frese, Tim C. Somervaille
Journal: Cancer Research (2023)

Abstract Background Inobrodib (CCS1477) is a first in class potent, selective, and orally bioavailable inhibitor of the bromodomains of p300 and CBP, two closely related histone acetyl transferases with oncogenic roles in hematological malignancies. In pre-clinical studies inobrodib potently inhibited cell proliferation in acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) cell lines. Inobrodib demonstrated dose-dependent efficacy in corresponding xenograft models, eliciting tumor regression at the highest doses. These effects were accompanied by significant reductions in expression of MYC, MYB and IRF4. Low doses of inobrodib also demonstrated good efficacy when added to standard-of-care treatments, providing a strong rationale for combination treatment in patients. Inobrodib represents a novel and differentiated approach and offers a potential new therapeutic option for patients who have relapsed or are refractory to current standard of care therapies in AML, higher risk MDS, MM or NHL. Study Design and Methods NCT04068597 is an adaptive multi-arm/multi-stage trial allowing exploration of p300/CBP inhibition as monotherapy or in combination with different agents across multiple indications including AML/higher risk MDS, MM, and NHL. The trial was initiated as a dose escalation rolling 6 design separately in AML/MDS and MM/NHL to ensure tolerability is explored separately across groups of indications, with the possibility to expand in monotherapy across different indications. Key inclusion criteria include patients with confirmed relapsed or refractory disease, with patients having received standard therapy (typically at least two prior lines of therapy). Response criteria are assessed using standard methodologies for the different indications. Blood and tumor samples are collected for exploratory biomarker analysis to understand mechanisms of response to treatment or disease progression. The recommended phase 2 dose/schedule has been determined, and monotherapy expansion arms are currently open in selected indications. Cohorts investigating dose escalation with standard of care agents pomalidomide/dexamethasone in MM as well azacytidine with or without venetoclax in AML or MDS are currently enrolling, with the possibility of expansion for promising combinations. An additional ‘rescue’ cohort for MM patient who failed inobrodib monotherapy will be used to determine whether addition of pomalidomide with or without dexamethasone may reverse resistance to inobrodib. This cohort will also explore tolerability and clinical activity of steroid-sparing combination regimen. Citation Format: Tomasz Knurowski, Emma Searle, Karen Clegg, Neil Pegg, William West, Debbie Haynes, Kristopher Frese, Tim C. Somervaille. An open-label phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy and in combination in patients with advanced hematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT136.